Alternative titles; symbols
HGNC Approved Gene Symbol: SKI
SNOMEDCT: 719069008;
Cytogenetic location: 1p36.33-p36.32 Genomic coordinates (GRCh38) : 1:2,228,319-2,310,213 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.33-p36.32 | Shprintzen-Goldberg syndrome | 182212 | Autosomal dominant | 3 |
Nomura et al. (1989) isolated human cDNA clones of SKI and a SKI-related gene, SNO (165340).
Doyle et al. (2012) performed a developmental survey of SKI expression in wildtype mice and observed that at embryonic day 13.5, SKI protein was robustly expressed throughout the vessel wall in the proximal ascending aorta with less expression in the descending segment and was localized to both the cytoplasm and nucleus. At birth, aortic expression was somewhat reduced, and SKI was predominantly localized to the cytoplasm. In adult mice (postnatal day 90), SKI expression was further reduced in the medial layer of the aortic root, with exclusive cytoplasmic localization; in the more distal ascending aorta, SKI expression was largely absent from the central zone of the aortic media, despite some residual expression in the intimal and adventitial layers. Doyle et al. (2012) suggested that SKI might be predominantly required in the very proximal aorta at early stages of development for the proper regulation of TGF-beta signaling within the arterial media.
Wu et al. (2002) determined the crystal structure of the SMAD4 (600993)-binding domain of SKI in complex with the MH2 domain of SMAD4 at 2.85-angstrom resolution. The structure revealed specific recognition of the SMAD4 L3 loop region by a highly conserved interaction loop (I loop) from SKI. The SKI-binding surface on SMAD4 was found to significantly overlap with that required for binding of the receptor-mediated SMADs (R-SMADs). Indeed, SKI disrupted the formation of a functional complex between the comediator SMADs (Co-SMADs) and R-SMADs, explaining how it could lead to repression of TGF-beta, activin (see 147390), and bone morphogenetic protein (see 112264) responses. The structure of the SKI fragment, stabilized by a bound zinc atom, resembled the SAND domain found in transcription factors and other nuclear proteins, in which the corresponding I loop is responsible for DNA binding.
Shinagawa et al. (2001) mapped the SKI gene to chromosome 1p36.3. Colmenares et al. (2002) confirmed the location of the gene in distal 1p36.3.
Transforming growth factor-beta (TGFB1; 190180) treatment of cells induces a variety of physiologic responses, including growth inhibition, differentiation, and induction of apoptosis. TGFB1 induces phosphorylation and nuclear translocation of SMAD3 (603109). Sun et al. (1999) described the association of SMAD3 with the nuclear protooncogene protein SKI in response to the activation of TGFB1 signaling. Association with SKI repressed transcriptional activation by SMAD3, and overexpression of SKI rendered cells resistant to the growth-inhibitory effects of TGFB1. The transcriptional repression as well as the growth resistance to TGFB1 by overexpression of SKI could be overcome by overexpression of SMAD3. These results demonstrated that SKI is a novel component of the TGFB1 signaling pathway and shed light on the mechanism of action of the SKI oncoprotein.
Experiments involving overexpression of Ski suggest that this gene is involved in neural tube development and muscle differentiation (Sutrave et al., 1990; Amaravadi et al., 1997; Kaufman et al., 2000). Ski -/- mice display a cranial neural tube defect that results in exencephaly and a marked reduction in skeletal muscle mass (Berk et al., 1997). Colmenares et al. (2002) showed that the penetrance and expressivity of the Ski -/- phenotype changes when the null mutation is backcrossed into the C57BL6/J background, with the principal change involving a switch from a neural tube defect to midline facial clefting. Other defects, including depressed nasal bridge, eye abnormalities, skeletal muscle defects, and digital abnormalities, show increased penetrance in the C57BL6/J background. Of note, these phenotypes resemble some of the features observed in individuals with 1p36 deletion syndrome (607872) (Shapira et al., 1997; Slavotinek et al., 1999). These similarities prompted Colmenares et al. (2002) to examine the chromosomal location of human SKI and to determine whether SKI is included in the deletions of 1p36. They found that human SKI indeed is located at distal 1p36.3 and was deleted in all of the individuals tested to that time who had the 1p36 deletion syndrome. Thus, SKI may contribute to some of the phenotypes common in 1p36 deletion syndrome, and particularly to facial clefting.
Shinagawa et al. (2001) also mapped the SKI gene to 1p36.3 and determined its relationship to the p73 tumor suppressor gene (TP73; 601990) which also maps to 1p36. They showed that loss of 1 copy of c-ski increases susceptibility to tumorigenesis in mice. When challenged with a chemical carcinogen, c-ski heterozygous mice showed an increased level of tumor formation relative to wildtype mice. In addition, c-ski-deficient mouse embryonic fibroblasts had increased proliferative capacity, whereas overexpression of c-ski suppressed the proliferation.
Okamoto et al. (2002) found that the SKI gene was deleted in a Japanese girl with the 1p36 deletion syndrome with manifestations of congenital fiber-type disproportion myopathy (CFTD; 255310) and dilated cardiomyopathy.
Atanasoski et al. (2004) found that overexpression of human SKI in cultured rodent Schwann cells inhibited TGFB1-mediated proliferation and prevented growth-arrested cells from reentering the cell cycle. Ski was upregulated in myelinating Schwann cells cocultured with dorsal root ganglion neurons, in myelinating mouse Schwann cells in vivo, and during remyelination after injury. Myelination was blocked in myelin-competent cultures derived from Ski-deficient mice, and genes encoding myelin components were downregulated in Ski-deficient nerves. Conversely, overexpression of Ski in Schwann cells caused an upregulation of myelin-related genes. Ski and Oct6 (602479), a transcription factor involved in myelination, appeared to mutually regulate each other. Atanasoski et al. (2004) concluded that expression of SKI is regulated by axon-Schwann cell interactions and that SKI is a crucial signal in Schwann cell development and myelination.
Zhang et al. (2017) demonstrated that TGF-beta enables TH17 cell differentiation by reversing SKI-SMAD4 (600993)-mediated suppression of the retinoic acid receptor (RAR)-related orphan receptor ROR-gamma-t (RORC; 602943). Zhang et al. (2017) found that, unlike wildtype T cells, SMAD4-deficient T cells differentiate into TH17 cells in the absence of TGF-beta signaling in a RORC-dependent manner. Ectopic SMAD4 expression suppresses RORC expression and TH17 cell differentiation of SMAD4-deficient T cells. However, TGF-beta neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the RORC locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGF-beta stimulation. SKI controls histone acetylation and deacetylation of the RORC locus and TH17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the RORC locus, RORC expression, and TH17 cell differentiation in a SMAD4-dependent manner. Therefore, Zhang et al. (2017) concluded that TGF-beta-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of ROR-gamma-t to enable TH17 cell differentiation.
In 10 of 12 sporadic patients with Shprintzen-Goldberg syndrome (SGS; 182212), Doyle et al. (2012) identified de novo heterozygous mutations in the SKI gene, including 8 missense mutations and one 9-bp deletion (see, e.g., 164780.0001-164780.0005). Cultured dermal fibroblasts from affected individuals showed enhanced activation of TGF-beta signaling cascades and higher expression of TGF-beta-responsive genes relative to control cells.
In 18 of 19 patients from 13 families with characteristic features of SGS, including 5 affected individuals over 3 generations in 1 family and another family in which 3 sibs were affected, Carmignac et al. (2012) identified heterozygosity for 2 different in-frame deletions and 10 missense mutations in the SKI gene (see, e.g., 164780.0002, 164780.0004, 164780.0005, and 164780.0007-164780.0010). All of the mutations were located in exon 1 of the SKI gene, within the R-SMAD-binding domain. No SKI mutations were found in a cohort of 11 patients with other marfanoid craniosynostosis syndromes.
Schepers et al. (2015) analyzed the SKI gene in 19 patients with clinically suspected SGS and identified 8 recurrent and 3 novel mutations in 11 patients (see, e.g., 164780.0002-164780.0004, 164780.0007; 164780.0010). The authors stated that their findings, in combination with previously reported data, clearly show a mutational hotspot in the SKI gene, with 24 (73%) of 33 unrelated patients having mutations within a stretch of 5 residues (from ser31 to pro35).
Doyle et al. (2012) generated zebrafish with morpholino-based knockdown of the 2 paralogs of mammalian SKI (skia and skib), and observed mutant embryos with marked craniofacial cartilage deficits, including shortened and flat Meckel cartilage, irregular lengths of palatoquadrates, shortened ceratohyales, and depleted ceratobranchial arches. These deficits manifested in larval fish as maxillary hypoplasia, malformed ethmoid plate, micrognathia, and microcephaly, and were frequently accompanied by ocular hypertelorism and spinal malformation. In addition, the skia- and skib-morphant embryos showed severe cardiac anomalies, characterized by partial to complete failure in cardiac looping and malformations of the outflow tract. Doyle et al. (2012) noted that in comparison to Ski-null mice, the zebrafish morphants more closely recapitulated the human craniofacial phenotype of Shprintzen-Goldberg syndrome.
Balazs et al. (1984) mapped the SK (for Sloan-Kettering) chicken viral oncogene to 1q12-qter. By in situ hybridization, Chaganti et al. (1986) regionalized the SKI gene to 1q22-q24.
In a 43-year-old woman with Shprintzen-Goldberg craniosynostosis syndrome (SGS; 182212), Doyle et al. (2012) identified heterozygosity for a de novo 347G-A transition in exon 1 of the SKI gene, resulting in a gly116-to-glu (G116E) substitution at a highly conserved residue in an exposed beta hairpin loop in the DHD domain. The mutation was not found in her unaffected parents or in SNP databases.
In a 12-year-old boy and an unrelated 22-year-old woman with Shprintzen-Goldberg craniosynostosis syndrome (SGS; 182212), Doyle et al. (2012) identified heterozygosity for a 94C-G transversion in exon 1 of the SKI gene, resulting in a leu32-to-val (L32V) substitution at a highly conserved residue in the SMAD2 (601366)/3 (603109)-binding domain. The mutation was not found in dbSNP (build 134), the 1000 Genomes Project database, or more than 10,000 exomes reported on the National Heart, Lung, and Blood Institute Exome Variant Server.
In 3 unrelated patients with SGS, Carmignac et al. (2012) identified heterozygosity for the L32V mutation in the SKI gene. One of the patients, a 32-year-old man, had aortic root dilation, mitral valve prolapse, and mitral insufficiency.
In a 50-year-old man with SGS, Schepers et al. (2015) identified heterozygosity for the L32V mutation in the SKI gene. The patient did not have mitral valve prolapse, aortic root dilation, or aneurysms.
In a 16-year-old boy with Shprintzen-Goldberg craniosynostosis syndrome (SGS; 182212), Doyle et al. (2012) identified heterozygosity for a 101G-A transition in exon 1 of the SKI gene, resulting in a gly34-to-asp (G34D) substitution at a highly conserved residue in the SMAD2 (601366)/3 (603109)-binding domain. The mutation was not found in dbSNP (build 134), the 1000 Genomes Project database, or more than 10,000 exomes reported on the National Heart, Lung, and Blood Institute Exome Variant Server.
In a sister and brother with SGS, Schepers et al. (2015) identified heterozygosity for the G34D substitution in the SKI gene. The mutation was not found in their unaffected parents, nor was there evidence for somatic mosaicism in the blood of the parents. Schepers et al. (2015) suggested that germline mosaicism was the most likely explanation for the occurrence of disease in 2 sibs from healthy parents. The 13-year-old boy exhibited aortic root dilation, whereas his 22-year-sister did not have any cardiovascular features.
In a 21-year-old man with Shprintzen-Goldberg craniosynostosis syndrome (SGS; 182212), Doyle et al. (2012) identified heterozygosity for a 100G-A transition in exon 1 of the SKI gene, resulting in a gly34-to-ser (G34S) substitution at a highly conserved residue in the SMAD2 (601366)/3 (603109)-binding domain. The mutation was not found in dbSNP (build 134), the 1000 Genomes Project database, or more than 10,000 exomes reported on the National Heart, Lung, and Blood Institute Exome Variant Server.
In an 11-year-old girl with SGS, whose features included aortic root dilation and mitral valve prolapse, Carmignac et al. (2012) identified heterozygosity for the G34S mutation in the SKI gene.
In a 10-year-old boy with SGS, Schepers et al. (2015) identified heterozygosity for a de novo G34S substitution in the SKI gene. He did not exhibit mitral valve prolapse, aortic root dilation, arterial tortuosity, or aneurysms.
In a 2-year-old girl with Shprintzen-Goldberg craniosynostosis syndrome (SGS; 182212), Doyle et al. (2012) identified heterozygosity for a 100G-T transversion in exon 1 of the SKI gene, resulting in a gly34-to-cys (G34C) substitution at a highly conserved residue in the SMAD2 (601366)/3 (603109)-binding domain. The mutation was not found in dbSNP (build 134), the 1000 Genomes Project database, or in more than 10,000 exomes reported on the National Heart, Lung, and Blood Institute Exome Variant Server.
In a 21-year-old woman with SGS, Carmignac et al. (2012) identified heterozygosity for the G34C mutation in the SKI gene.
In a 5-year-old boy with Shprintzen-Goldberg craniosynostosis syndrome (SGS; 182212), Doyle et al. (2012) identified heterozygosity for a 9-bp deletion in exon 1 of the SKI gene (283_291del9), resulting in removal of 3 highly conserved residues (asp95-ser97del) in the DHD domain. The mutation was not found in dbSNP (build 134), the 1000 Genomes Project database, or more than 10,000 exomes reported on the National Heart, Lung, and Blood Institute Exome Variant Server.
In 22-year-old female twins and their 20-year-old sister who had Shprintzen-Goldberg craniosynostosis syndrome (SGS; 182212), Carmignac et al. (2012) identified a heterozygous 101G-T transversion in exon 1 of the SKI gene, resulting in a gly34-to-val (G34V) substitution at a conserved residue within the R-SMAD-binding domain. The mother had the mutation in somatic mosaic state. The mutation was not found in the dbSNP or Exome Variant Server databases.
In a 44-year-old woman with SGS, Schepers et al. (2015) identified heterozygosity for the G34V substitution in the SKI gene.
In 5 affected individuals over 3 generations of a family with Shprintzen-Goldberg craniosynostosis syndrome (SGS; 182212), Carmignac et al. (2012) identified heterozygosity for a 12-bp deletion (280_291delTCCGACCGCTCC) in exon 1 of the SKI gene, resulting in an in-frame deletion within the R-SMAD-binding domain. The mutation was not found in the dbSNP or Exome Variant Server databases.
In an 18-year-old man with Shprintzen-Goldberg craniosynostosis syndrome (SGS; 182212), Carmignac et al. (2012) identified heterozygosity for a 104C-A transversion in exon 1 of the SKI gene, resulting in a pro35-to-gln (P35Q) substitution at a conserved residue within the R-SMAD-binding domain. The patient had dilation of the aortic root requiring surgery at 16 years of age, and also had vertebrobasilar and internal carotid tortuosity, mitral valve prolapse, and a dilated pulmonary artery root. The mutation was not found in the dbSNP or Exome Variant Server databases.
In a 21-year-old woman with Shprintzen-Goldberg craniosynostosis syndrome (SGS; 182212), Carmignac et al. (2012) identified heterozygosity for a 103C-T transition in exon 1 of the SKI gene, resulting in a pro35-to-gln (P35Q) substitution at a conserved residue within the R-SMAD-binding domain. No aortic root dilation or valvular anomalies were reported in this patient. The mutation was not found in the dbSNP or Exome Variant Server databases.
In a 4-year-old girl and an unrelated 10-year-old girl with SGS, Schepers et al. (2015) identified heterozygosity for a P35S substitution in the SKI gene. The mutation occurred de novo in both cases. Neither patient exhibited mitral valve prolapse, aortic root dilation, arterial tortuosity, or aneurysms.
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